Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive

Seon Hee Kim, Nicole Bianco, Rajasree Menon, Eric R. Lechman, William J. Shufesky, Adrian E. Morelli, Paul D. Robbins

Research output: Contribution to journalArticlepeer-review

164 Scopus citations

Abstract

We previously have demonstrated the ability of primary murine bone marrow-derived DC (BM-DC), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) following systemic delivery. Here we demonstrate that exosomes derived from genetically modified BM-DC expressing FasL are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH). Local administration of exosomes derived from DC expressing FasL (Exo/FasL) as well as the parental DC/FasL resulted in a significant reduction in swelling in both the treated and the untreated distal paw. However, both the DC/FasL and the Exo/FasL were unable to suppress the DTH response in lpr (Fas-deficient) mice. Gene transfer of FasL to BM-DC from gld (FasL-deficient) mice resulted in restoration of the ability of DC as well as DC-derived exosomes to suppress DTH. The ability of DC-derived exosomes and DC to suppress DTH responses was antigen specific and MHC class II dependent, but class I independent. The injected exosomes were found to be internalized into CD11c+ cells at the site of injection and in the draining popliteal lymph node. Systemic injection of exosome/FasL into mice with established CIA resulted in significant disease amelioration. These results demonstrate that both systemic and local administration of exosomes derived from FasL-expressing DC are able to suppress antigen-specific immune responses through an MHC class II-dependent pathway, resulting in effective and sustained treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. These results suggest that DC/FasL-derived exosomes could be used clinically for the treatment of inflammatory and autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)289-300
Number of pages12
JournalMolecular Therapy
Volume13
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants AI 56374 (P.D.R.), HL 75512 (A.E.M.) and HL 77545 (to A.E.M.) from the National Institutes of Health.

Keywords

  • Autoimmune disease
  • Dendritic cells
  • Exosomes
  • Fas ligand
  • Suppression

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